DESCRIPTION(provided by applicant): Telomere shortening has been causally linked to cellular senescence in different species, and in humans, telomere shortening has been associated with aging and poorer survival. In addition, prior genetic studies suggest that telomere length is heritable. We hypothesize that telomere shortening is associated with aging, and it is variable and heritable in the Old Order Amish (OOA). The primary objectives of this research proposal are three-fold: (1) to examine whether shorter telomere lengths (TLs) are positively associated with aging at a population level; (2) to characterize genetic epidemiology of TLs and, (3) to identify genetic markers associated or linked to TLs. Telomere lengths will be measured using a newly developed and validated quantitative-PCR method. Information on TL measurements and age-related phenotypes will be obtained from 1,300 individuals in ongoing studies in the OOA. These subjects, who are participants in other studies, have been or will be extensively characterized with regards to traits related to cardiovascular diseases, metabolic syndrome, osteoporosis, and inflammation. Furthermore, data from a 5-cM genome-scan are already available in 1,000 study participants, which allow us to conduct a genome-wide linkage study searching for loci related to TL. No additional funding will be required for phenotypic characterization of age-related traits or genotyping for genome-wise scan in this proposed study. This proposed study will hopefully provide Insight into the association between telomere length and aging in humans and help in evaluating whether telomere length can be used as a biological marker of aging. Any positive findings will encourage further investigation into the biological relationship between TLs and aging. Unraveling the genetic pathways involved in the regulation of telomere length will have important and farreaching implications in understanding many aspects of human health and diseases. Such knowledge may also aid in the development of regenerative medicine, cultured tissue transplantation, and stem cell therapeutics.